DK155084B - METHOD OF PREPARING META-ARYLOXY-BENZALDE HYDERS - Google Patents

Description

DK 155084 B

The present invention relates to a particular process for the preparation of meta-aryloxy-benzaldehydes, which compounds are valuable intermediates, for example, in the preparation of pesticides containing a meta-aryloxy-benzyl group. Such pesticides are e.g. meta-aryloxybenzyl esters of substituted cyclopropane carboxylic acids and chlorophenyl acetic acids which have excellent insecticidal properties.

One possible way to prepare a meta-aryloxy-benzaldehyde is to halogenate the corresponding meta-aryloxy-toluene to form the benzyl halide and then convert this halide to the benzaldehyde.

Thus, e.g. known from Kirk-Othmer, Encyclopedia of Chemical Technology, 2nd ed. Volume 3, 1964, p. 362, to prepare benzaldehyde from benzyl chloride in the Sommelet reaction, e.g. by reacting benzyl chloride with hexamethylenetetramine and hydrolyzing the resulting product under acidic conditions to form benzaldehyde. However, while this synthetic route is satisfactory in principle, it suffers from various deficiencies, namely (i) the necessity of regulating the conditions of the halogenation step to obtain the maximum yield of benzyl halide at the expense of the total yield of other halogenated products (e.g. benzal halide and ring halogenated products), and (ii) the yield of benzyl halide rarely exceeds 70%.

It has now been found that these disadvantages can be significantly mitigated by using a modified process which allows the conversion of mixtures of side chain halogenated meta-aryloxy toluene, namely a mixture of benzyl and benzal halides, to the aldehyde.

The present invention therefore relates to a process for the preparation of meta-aryloxy-benzaldehydes which is characterized by reacting in a first step a mixture of the corresponding meta-aryloxy-benzyl and -benzal halides with ammonia and formaldehyde or with hexamethylenetetramine. and in a second step, the resulting product hydrolyses under acidic conditions to form the meta-aryloxy-benzaldehyde.

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Instead of ammonia and formaldehyde, hexamethylenetetramine can be used in the first step of the process of the invention, and it will be understood that the use of hexamethylenetetramine gives a similar result due to the chemical equilibrium that exists between hexamethylenetetramine and ammonia and formaldehyde. Thus, ammonia and formaldehyde may be considered as precursors of hexamethylenetetramine, or hexamethylenetetramine may be considered as ammonia and formaldehyde generators.

Although aqueous conditions are not essential for the first step of the process of the invention and reaction can be obtained in a non-aqueous solvent such as chloroform, aqueous conditions can conveniently be used for the hydrolysis reaction of the second step of the process. Aqueous ammonia, aqueous formaldehyde or aqueous hexamethylenetetramine can therefore be used. The first step of the process is an exothermic reaction, and therefore no heat is usually required to initiate the reaction; reaction temperatures in the range of 10 to 150 ° C can be conveniently used in practice.

The product of the first step of the process of the invention is a mixture containing a benzyl halide complex salt and substantially unchanged benzal halide; both of these products can be isolated and then subjected to a hydrolysis procedure, but it has been found that this is unnecessary and that hydrolysis of the reaction mixture from the first step proceeds smoothly and efficiently. The hydrolysis is preferably carried out at a pH in the range of 3 to 6.5, and better results are obtained at a pH in the range of 5 to 6. The acid used to obtain these pH values may be an organic or inorganic acid, and suitable examples thereof are acetic acid, phosphoric acid, hydrochloric acid or sulfuric acid; acetic acid has been found to be particularly suitable for this, especially 50% acetic acid. The hydrolysis may be carried out by refluxing the acidified reaction mixture or in any other convenient manner; temperatures in the range of 80 to 200 ° C are generally suitable, and temp. temperatures in the range of 80 to 120 ° C are preferred.

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It has been found that the first step of the process of the invention can be carried out in the presence of the acid used in the hydrolysis step and that better yields are obtained in this way. Eg. For example, the first step may be carried out by adding the benzyl and benzal halide to a solution of hexamethylenetetramine dissolved in acetic acid and refluxing the resulting mixture.

It has also been found that the hydrolysis reaction can be facilitated by the presence of a mineral acid, e.g. hydrochloric acid, and it may be added in the first or second steps of the process of the invention, or, if desired, towards the end of the hydrolysis reaction.

A significant advantage of the process of the invention is that it can be applied to mixtures of benzyl and benzal halides in any ratio. Since the existing economic synthesis pathways for the production of the benzyl halide result in the simultaneous formation of some dihalide, ie. any benzal halide, the present invention allows these mixtures to be converted to the corresponding benzaldehyde without the need to separate and remove the dihalide. It is noteworthy that the dihalide is not appreciably affected during the reaction in the first step of the process of the invention and that it, together with the benzyl halide complex, is hydrolyzed to form the desired aldehyde in the second step.

Excellent results in aldehyde yield have been obtained with mixtures of the benzyl and benzal bromide and benzyl and benzal chloride.

The benzyl and benzal halide mixture can be prepared in any convenient manner, although it has been found that such a mixture can be readily prepared by a halogenation reaction to the corresponding toluene. The mixture of meta-aryloxybenzyl halide and benzal halide used as starting material in the process of the invention can be prepared by a process which comprises halogenation at elevated temperature in the presence of a free radical.

DK 155084 B

radical initiator. The temperature of the halogenation reaction depends very much on the nature of the halogen used and the need to avoid ring halogenation of the toluene. A usual temperature range of the halogenation reaction is 50 - 250 ° C.

Concerning the bromination, it has been found that good results are obtained by contacting the meta-aryloxy-toluene with gaseous bromine at a temperature in the range of 180 - 250 ° C, preferably in the presence of ultraviolet light as a free radical initiator. To obtain maximum total yields of benzyl and benzal bromide, a molar excess of the gaseous bromine is preferably used, e.g. at least 10% excess and usually at least 25% excess calculated on the molar amount of the starting toluene; molar excess in the range of 10 to 30% can generally be used. The use of such an excess of bromine inevitably results in the formation of a greater proportion of the benzal bromide than when a stoichiometric amount or a small molar deficit of bromine is used. However, since the process of the invention can readily convert both mono- and dibromides to the corresponding aldehyde, the presence of a larger proportion of dibromide in the resulting brominated mixture presents no problems. By this way, total yields of benzyl and benzal bromides of over 90% can be obtained.

With regard to the chlorination of the meta-aryloxy-toluene, it has been found that good results are obtained when the meta-aryloxy-toluene is contacted with gaseous chlorine in a non-polar solvent at a temperature in the range of 40 to 100 ° C. , the radical initiator being preferably a peroxide or an azo initiator, e.g. benzoyl peroxide or azo-isobutyronitrile (AIBN).

The non-polar solvent used for this chlorination reaction must be one which does not promote the formation of ring chlorinated products and is itself essentially unaffected by the prevailing chlorination conditions. Generally, halogenated hydrocarbons are satisfactory solvents for this reaction, e.g. carbon tetrachloride and chlorobenzene.

Excellent results have been obtained with carbon tetrachloride as the solvent. To promote the side chain chlorination of toluene and suppression of ring chlorination, it has been found suitable

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to prevent chlorination of the toluene at high concentrations, e.g. more than 60% by weight of toluene in the solvent; concentrations in the range of 5 to 50% by weight have generally been found to be appropriate. Furthermore, the conversion of toluene should not be allowed to end, as this tends to yield undesirable chlorination products; the reaction should thus be interrupted by a conversion in the range of 95 - 99%, based on meta-aryloxy-toluene, conveniently 98 or 99%. As with the bromination reaction, the total yields of mono and dichloride are usually above 90% and often above 95%.

The nature of the meta-aryloxy substituent in the starting material and in the product of the process of the invention is not essential, but the most commercially important product, given its importance in the synthesis of synthetic pesticide-active pyrethroids, is meta-phenoxy-benzaldehyde.

Therefore, it will be appreciated that the present invention provides a valuable synthetic route to meta-phenoxy-benzaldehyde from meta-phenoxy-toluene without the need for isolation of a particular intermediate chloride or bromide for conversion to the aldehyde. An important advantage of the process is its flexibility in its ability to convert a mixture into any ratio of meta-phenoxy-benzyl halide to meta-phenoxy-benzal halide (i.e., a mixture of the mono- and dihalo-genide ) to the desired aldehyde.

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Examples 1b, 2, 3, 4 and 8 illustrate the invention, while Examples 1a and 5-7 illustrate the preparation of the compounds used as starting materials.

Example 1.

a) Preparation of meta-phenoxy-benzyl and -benzal bromide.

430 g (2.337 mole) of 3-phenoxytoluene is treated with a stream of bromine (473 g, 2.956 mole) of nitrogen atmosphere in a 5 liter container containing an ultraviolet light source designed to introduce the bromine near the UV source , and the reactants are vigorously circulated. Thus, the bromine is present in a 26.5% molar excess relative to phenoxytoluene. When the addition is complete (about 3 hours), the reaction mixture is allowed to cool overnight while being rinsed with a stream of nitrogen. There are thus obtained 627 g of brominating product of the following composition: 3-phenoxytoluene (unchanged) 2.1% 3-phenoxybenzyl bromide 61.5% 3-phenoxybenzal bromide 36.4%.

b) Preparation of meta-phenoxy-benzaldehyde.

The bromination mixture obtained from the above point (a) is added to 1 liter of glacial acetic acid and 350 g of hexamethylenetetramine (2.5 mol), after which 1 liter of water is added. The mixture is refluxed (105 ° C) for 4 hours, then 500 ml of concentrated hydrochloric acid is added and then, 5 minutes later, 700 ml of water, and the mixture is refluxed for a further 15 minutes.

After cooling to room temperature by immersing in ice water, the reaction mixture is extracted with 3 x 500 ml of methylene dichloride.

The combined extracts are washed to neutral reaction (pH 7-8) with saturated sodium bicarbonate solution and then washed once with 1 liter of ice-cold aqueous 10% hydrochloric acid and once again

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with 1 liter of water. After drying over anhydrous sodium sulfate, the methylene dichloride is distilled off and the remaining product is degassed to constant weight under high vacuum (0.1 mm Hg) to give 430.5 g (2.172 mole) of 3-phenoxy-benzaldehyde.

NMR analysis of this product shows that it has a purity of 95% and gas-liquid chromatographic analysis shows that all the benzyl bromide and benzal bromide have reacted. The yield of 3-phenoxy-benzaldehyde (2.172 moles) is 93% of the theoretical, based on the starting product used as 3-phenoxytoluene (2.337 moles).

Example 2.

Preparation of meta-phenoxy-benzaldehyde from the corresponding benzyl and benzal bromide.

33.65 g of brominated m-phenoxytoluene prepared as described in Example 1 a) is added to a solution of 16.8 g of hexamethylene tramine in 140 ml of chloroform. The mixture is stirred overnight, then filtered; there is obtained 41.5 g of product which is dissolved in 35 ml of acetic acid and 35 ml of water and heated under reflux for 4 hours. After the addition of concentrated hydrochloric acid (27 ml), the reflux is maintained for an additional 0.5 hour. The cooled reaction mixture is extracted with methylene chloride (3 x 20 ml) and the organic extract washed neutral with aqueous sodium bicarbonate solution, then the solvent is evaporated and the residue is distilled to give 14.6 g (61% of theory) of m-phenoxybenzaldehyde. in the form of a colorless liquid with a boiling point 140 - 141 ° C / 1 mm Hg.

Example 3

Preparation of meta-phenoxy-benzaldehyde from the corresponding benzyl and benzal chloride.

A mixture of 3-phenoxybenzyl chloride and 3-phenoxybenzal chloride (50 g) containing 60% monochloride and 40% dichloride is added.

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a solution of 35 g of hexamethylenetetramine dissolved in 100 ml of acetic acid. Water (100 ml) is added and the mixture is heated at reflux for 4 hours. Concentrated hydrochloric acid is then added and the mixture refluxed for a further 15 minutes.

After cooling to room temperature, the reaction mixture is extracted with methylene chloride (3 x 50 ml). The combined extracts are washed for neutral reaction with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and then evaporated to give 41.9 g of 197% of theoretical 3-phenoxybenzaldehyde.

Example 4

Preparation of meta-phenoxy-benzaldehyde from the corresponding benzyl and benzal bromide.

A solution of formaldehyde (40%, 50 ml) is cooled to 10 ° C and then treated with 25 ml of 35% aqueous ammonia solution for 15 minutes.

25 g of crude bromide mixture prepared as described in Example 1 a) are added and the mixture is stirred for 4 hours under a nitrogen atmosphere. The mixture is then acidified with 50 ml of acetic acid and heated for 3 hours under reflux. After cooling, the reaction mixture is extracted with 25 ml of toluene and the extract washed to neutral reaction with sodium bicarbonate solution. The crude 3-phenoxybenzaldehyde toluene solution is diluted with an equal amount of ethanol and then stirred with a saturated aqueous solution of sodium bisulfite. The resulting bisulfite compound is filtered off and washed with toluene until it is free of colored impurities. After vacuum drying, there is thus obtained 20.5 g of purified 3-phenoxybenzaldehyde bisulfite compound which gives diluted mineral acid treatment to give the pure 3-phenoxybenzaldehyde. The yield, based on bromide blending, is 77% of theoretical.

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Examples 5-7.

Preparation of a mixture of meta-phenoxybenzyl chloride and meta-phenoxybenzal chloride.

Chlorine is bubbled to a refluxing solution (80 ° C) of 10 g of meta-phenoxy-toluene and 0.25 g of initiator in 100 ml of carbon tetrachloride as solvent. A series of experiments with different reaction times and different initiators are performed and the results are shown in Table I.

From these results, it will be seen that the selectivity (i.e., the sum of the weight percent of mono- and dichloride) depends on the presence of a free radical initiator and on the avoidance of complete conversion of the toluene (cf. Example 6, where the selectivity is relatively poor when the reaction is allowed to proceed to complete conversion).

In another series of experiments, it is shown that the selectivity also depends on the concentration of toluene in the solvent, namely that the selectivity decreases with increasing toluene concentrations.

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Claims (6)

Example 8 Preparation of meta-phenoxy-benzaldehyde from the corresponding benzyl and benzal chloride. A solution of formaldehyde (40%, 150 ml) is cooled to 10 ° C and then treated for 15 minutes with 75 ml of 35% aqueous ammonia solution. A mixture of 3-phenoxybenzyl chloride and 3-phenoxybenzal chloride containing 70% monochloride and 30% dichloride (50 g) is added and the mixture is stirred for 3 hours under a nitrogen atmosphere. The mixture is then acidified with 150 ml of acetic acid, stirred for an additional 3 hours in the cold and then refluxed for 4 hours. After cooling, the reaction mixture is extracted with 100 ml of toluene and the extract washed to neutral reaction with sodium bicarbonate solution. The crude 3-phenoxy-benzaldehyde toluene solution is diluted with an equal amount of ethanol and then stirred with a saturated aqueous sodium bisulfite solution. The resulting bisulfite adduct is filtered off and washed with toluene. After vacuum drying, there is obtained 63.0 g of purified 3-phenoxybenzaldehyde bisulfite compound which, upon treatment with dilute mineral acid, gives the pure 3-phenoxybenzaldehyde. The yield, calculated on the chloride mixture, is 95% of theoretical. A process for preparing meta-aryloxy-benzaldehydes, characterized in that in a first step, a mixture of the corresponding meta-aryloxy-benzyl and -benzalhalides with ammonia and formaldehyde or with hexamethylenetetramine is reacted and, in a second step, hydrolyzes the resulting product under acidic conditions to form the meta-aryloxy-benzaldehyde. Process according to claim 1, characterized in that the first step is carried out under aqueous conditions. Process according to claim 1, characterized in that the hydrolysis step is carried out at a pH in the range 3 - 6.5. 12 DK 155084 B Process according to claim 3, characterized in that the hydrolysis step is carried out in the presence of acetic acid. Process according to claim 1 or 3, characterized in that the hydrolysis step is carried out in the presence of mineral acid. Process according to claims 1 or 3-5, characterized in that the acid or acids used in the hydrolysis step are present in the first step of the process.